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oranges and one lemon per day added to
rations prevented scurvy. Unfortunately, this
finding subsequently also led to the first
“debunking” of a vitamin based treatment for
he story of
disease. As fresh fruit was difficult to store
Vitamin C then
on long voyages, Dr. Lind recommended a
begins with the
lemon juice concentrate known as “rob”. Rob
disease of scurvy.
was prepared by prolonged boiling of lemon
Hippocrates first described this often fatal
juice in copper pots, a process which
vitamin deficiency disease some 2,500 years destroyed most of the vitamin C, hence
ago noting that it was characterized by
discrediting Dr. Lind’s position on fresh
bleeding gums, hemorrhaging and death.
citrus fruits. Eventually, however, the Royal
While not a pretty picture, clinical scurvy is
Navy did begin to appreciate the utility of
also thankfully, somewhat rare in the general fresh citrus fruits to prevent scurvy and
population as vitamin C may be found in both adopted lemons or limes as part of standard
plant and animal sources. Nonetheless, a diet rations. This practice led to the American
devoid of fresh fruits, vegetables and fresh
nickname of “limey” for a British sailor.
meats if eaten for extended periods will lead
to disease. One such environment historically By this time it was
was long ocean going voyages where scurvy clear that some part
often took a horrendous toil and by some
of the diet present in
researchers estimates killed over a million
some foods and not
sailors between 1500 and 1700.1 In 1499
others, prevented
Vasco Da Gama lost some two thirds of his
scurvy. British
crew to scurvy, in 1529 Magellan lost 208 of explorer James Cook
230 crew, primarily to scurvy.2
embarked on a three
year journey, losing
Legend has it that the use of fresh fruit to
none of his men to
reverse scurvy was the result of a voyage of
scurvy by including sour krout in the rations.5
3
Christopher Columbus. Some of his sailors From these findings the idea of an antiwho were developing scurvy asked to be
scorbutic factor in the diet took hold.
dropped off on a Caribbean island rather than However, the level of understanding
die of disease at sea. When Columbus
remained at this level for over 200 years until
returned to the island some months later he
another fortunate accident. In 1907, two
was amazed to find the men, who had been
Norwegian physicians were attempting to
eating the fruits of the island, hearty and hale. create an animal model for the sailor’s
Hence he named the island Curacao, or
disease “beriberi”, a deficiency of vitamin
“cure” in Portuguese. This fortunate accident B1. (Gee I wonder if diet and vitamins could
led to an understanding that fresh fruit was a play any role in disease?). Leaving aside my
necessary part of the sailor’s diet.
sarcasm, by chance the physicians chose
guinea pigs to feed their bland diet to and
Some 200 years later in 1747, inquiry into the were amazed when the guinea pigs developed
cause of scurvy led to what is sometimes
scurvy instead of beriberi. The choice of
described as the first controlled clinical trial
guinea pig was fortuitous in that it was one of
in medicine.4 British Royal Navy ship’s
the few animals, along with primates, that
surgeon James Lind, while at sea, divided the does not manufacture its own vitamin C. So
crew into six groups each receiving an
there was now an animal model for the
addition to the diet that had been previously
disease of scurvy to use to test and try to
reported as effective in preventing scurvy.
isolate the anti-scorbutic factor.
From this experiment he concluded that two

History:

T

From diseases such as scurvy, beriberi,
rickets and others, the idea of a “vital amine”
or vitamin was proposed to explain the
accumulating dietary cures of disease. While
most vitamins turned out not to be amines,
the name stuck and is really a lot easier to use
than, “necessary organic micronutrient which
must be obtained in trace amounts from the
diet for health.”

the production of norephinephrine,
stabilization of peptide hormones and
modulation of tyrosine metabolism.

Vitamin C, as biologically active molecules
go, is a remarkably simple molecule and so
by 1934 a means of cheaply mass producing
it had already been devised, a process which
has remained basically unchanged down to
the present. This structural simplicity of
vitamin C though belies a complex role in
physiology. There are 8 distinct enzymes that
we know of to date where vitamin C is a
necessary co-factor for the enzyme to
function.6 The best known of these are three
that are involved with collagen synthesis. It
is the loss of function of these enzymes and
the subsequent inability to make connective
tissue collagen that leads to death from
scurvy in severe, prolonged vitamin C
deficiency. Vitamin C also is necessary for
the production of carnatine which is itself
needed to produce energy in the cell’s
mitochondria. Vitamin C is also involved in

If we look back at the history of vitamin C
being discerned as the cure for scurvy,
medical historian Peter Whitehead had this to
say,

None of these functions gives us a clear
understanding of how on a biochemical level,
vitamin C might be useful in cancer therapy.
Here a few points are in order. 1) we
obviously don’t understand cancer itself very
well as it continues to exact such a toll on
In 1931 a brilliant researcher by the name of health. 2) It was only 80 years ago that we
Albert Szent-Györgyi had isolated an
even identified vitamin C, so we are making
unknown compound called “hexuronic acid” rapid progress in research and undoubtedly
from animal adrenal glands. He suspected
have much more to learn. And 3), by way of
this hexuronic acid might be the long sought illustration, Dr. Szent-Gyorgi who isolated
after anti-scorbutic factor and sent a sample
vitamin C, started his career at the
to Charles King’s lab in Pittsburg. There Dr. Semmelweis University. Those who follow
King tested the substance in the formerly
my blog, The Skeptic's Health Journal Club,
developed guinea pig animal model and
and many others I’m sure, will recognize that
demonstrated that indeed this was the case.
name, Dr. Semmleweiss is the “Father of
The now isolated anti-scorbutic factor was
Antisepsis” and the physician who presented
renamed at this point from hexuronic acid to meticulous research that washing hands
ascorbic (i.e. “anti-scorbutic” acid) or as it is before delivering babies would end child-bed
more commonly called vitamin C. For his
fever. However, because there was not a
work in isolating vitamin C, as well as his
theory for why he was getting his results, they
work with Dr. Hans Adolph Krebs in defining were dismissed and tens if not hundreds of
the well known “Krebs Cycle” Dr. Szentthousands of women died after childbirth as a
Gyorgi received the 1937 Nobel prize in
result, while the “father of antisepsis” died in
medicine.
a mental hospital in his 40s.

"... By the start of the seventeenth
century, Lancaster was dosing his
sailors with spoonfuls of lemon juice,
and for a while this was continued on
East India Company ships. On the
face of it, the problem seemed to have
been solved, yet the literature shows
that again and again the lesson was
lost, buried by every kind of
obfuscation that medicine, prejudice,
and perhaps parsimony could
produce. The major hindrance was
undoubtedly theory. …"1
I say all this to acknowledge that we do not

have a clear theory for why vitamin C is
useful in cancer, nonetheless and in spite of
this we should keep an open and unbiased eye
to what the reality of the medical evidence is
telling us. In medicine we delve into this
reality through bench research, animal studies
and human trials. Of these the human studies
are always the gold standard as eventually all
the theory research and animal experiments
must come down to giving a drug or
intervention and seeing if someone gets better
or not. We will discuss this evidence
momentarily, but I would also now back up
and say there is, in addition to its role as an
enzymatic co-factor, another property of
vitamin C, that, though not certain, many
believe is tied into its usefulness as an anticancer therapy. Vitamin C is a powerful antioxidant.

Biochemistry

H

owever, even before getting to that let’s

back up for a moment and talk a bit more
about vitamin C’s structure and it’s
production in-vivo (i.e. how it is made in
living organisms themselves). If we take a
look at vitamin C, as compared with say a
500 amino acid long protein or lengthy DNA
sequence, there is not much to it.
Figure 1: Molecular Structure of Vitamin C

It is a six carbon molecule, in a 5 membered
ring with a number of hydroxyl groups
attached. Actually it looks pretty close to
some of the simple sugars we eat as part of

our diet. For example we can compare it with
the structure of glucose.
Figure 2: Molecular Structure of Glucose

Again we have a six carbon molecule, this
time in a six membered ring with a number of
hydroxyls attached.
Vitamin C, even as vitamins go is rather
unique from a number of perspectives. As I
alluded to earlier, for the vast majority of
animals as well as plants, vitamin C is not a
vitamin at all. They consider it so important
they manufacture it themselves.7 Only
primates, guinea pigs, fruit bats, and perhaps
a few other animals are unable to make
vitamin C.
Vitamin C is manufactured from that most
ubiquitous, “energy currency” molecule of
cells, you guessed it, glucose. This is done in
an enzymatically-controlled four step process.
It is interesting to note that humans have the
enzymes for the first three steps in the process
and are only missing the final enzyme.
Whether we have always lacked the ability to
make vitamin C or whether, as researchers
speculate,8 it dropped out at some point in our
evolution (perhaps sometime after the death
of 969 year old biblical patriarch Methuselah
- joking there - I think), is at present an open
question,
If we consider now to what extent animals
make use of vitamin C, it is to my mind rather
astonishing. An adult goat on an average day
will make 13,000 milligrams of vitamin C per
day,9 and will increase this number greatly if
stressed.10 That figure may be compared with

the, revised upward in 2000, recommended
daily allowance (RDA) of vitamin C of 90
milligrams per day for an adult male. Now
the RDAs are certainly a subject of debate
and revision. It is known approximately what
level will produce a clinically apparent
vitamin deficiency disease such as scurvy.
From there health authorities estimate a good
figure to mention to provide a margin of
safety to avoid the known deficiency disease.

Why on God’s green earth are goats
manufacturing levels of vitamin C, when in
perfect health, about 100 times greater than
we would think they need to prevent disease?
Do they just really, really, really want to be
on the safe side? The answer to this question
is not clear but it likely goes back to vitamin
C’s anti-oxidant properties.

“Anti-oxidant" is a term that is now almost
universally bandied about, however, the
While this is certainly a step in the right
science underlying all this dates back only a
direction especially as compared to losing
few decades and while intuitive remains very
whole crews of ocean going ships in centuries sparse on specifics. So to understand vitamin
past, vitamin proponents argue that we do not C’s usefulness as an anti-oxidant we might
know the levels for optimal health.
start by asking well what is the problem with
Subclinical disease may occur, or
oxidation?
manifestations of clinical disease that are
simply not being recognized as deficiency
While the class of oxidation/reduction
related, they argue, may occur at RDA levels. reactions is an extremely broad one, indeed a
While getting off topic I would suspect that
whole sub-discipline of chemistry, an
we are seeing an enormous example of this
example that we might use in terms of
unfolding before our eyes in terms of the
biological significance would be if you leave
effect of more elevated levels of vitamin D on a cut apple slice out on a plate. Over time
infectious viral diseases such as influenza.
you notice the surface of the cut area has
turned brown. This is because oxygen from
Be all that as it may, if all vitamin C is doing the air has bound irreversibly with molecules
is serving as an enzymatic co-factor, even if
in the apple. An analogous process occurs
there are additional enzymes involved that we more slowly with iron, we call that rust. So
don’t know of yet, let's triple the current
oxidation might be thought of as biological
RDA. Shouldn't that avoid all clinical and
rust. Oxygen itself is reactive as an oxidant
likely sub-clinical disease. So let’s see our
and may be part of compounds such as
RDA is now at 270 mg/day … that still is
hydrogen peroxide and others which are even
quite a bit less than the 13,000 mg/day made more reactive and powerful oxidants than
by the 150 lb goat. What is going on here?
itself. We make use of this reactivity of
oxygen as a fuel source, exhaling the carbon
In addition to making even more than this if dioxide as an end-product, so we are in a bit
sick, there is another very important point that of a catch 22 as regards having to deal with
we will return to again later. The goat is
oxygen's reactivity.
releasing this vitamin C, right from its liver
directly into its blood stream. While one
A common theme then of powerful oxidants,
cannot fully absorb 13,000 mg/day of vitamin whether they actually contain oxygen or only
C from the GI tract, by a conservative
increase the oxidative state is that they are
estimate, putting vitamin C into the blood
are highly reactive. Very strong oxidants, in
stream as opposed to ingesting it, leads to
turn often have an unpaired electron in their
blood levels an order of magnitude higher.
outer valence shell. These free-radicals, as
That is to say, if it could be absorbed it would they have been termed, have the annoying
be the equivalent of 130 grams of oral
habit of wanting so much to get rid of their
vitamin C per day!
unpaired electron that they bind to another
molecule, steal one of their electrons, and

thus turn the new molecule into a free radical
itself.

to poison the cancer cells of the patient, and
your medicine is getting in the way.” The
good news in this area is that, whatever turns
There are molecules however, which are able out to be the correct biochemical theory,
to bind to reactive free radicals without
vitamin C has been found repeatedly, as we
themselves turning into reactive molecules.
will get back to later, in test tube studies to
Such substances are knows as “anti-oxidants” potentiate, not diminish the effects of many
or “free-radical scavengers” and by lassoing conventional chemotherapeutic agents.
and tying up rampaging free radicals they
prevent damage to important biological
Others have proposed that vitamin C may at
molecules such as lipids, hormones, enzymes, very high doses not act as an anti-oxidant at
and DNA itself. It is not that far of a stretch all, but as a pro-oxidant (see figure 3) that
to look at anti-oxidants a little bit like octane selectively harms cancer cells through
boosters in gasoline. One needs to have the
creation of hydrogen peroxide.
highly reactive oxygen around to burn as fuel
but having enough anti-oxidants on board
Even more recently some interesting work in
ensures a cleaner burning engine.
this area was published in the Lancet in 2002.
Researchers note that hydrogen peroxide
From its ubiquitous use throughout so much itself has signaling properties which promote
of life, and as noted being manufactured in
cancer and when neutralized by the antilarge doses by most animals, vitamin C can
oxidant properties of a molecule such as
be seen as one of the antioxidants par
vitamin C this signal is interrupted. As lead
excellence. It is a small, water soluble
author Dr Lee comments,
molecule that can (for most animals) be easily
manufactured from glucose, can penetrate
"Vitamin C prevents the inhibition of
into all tissue areas and is incredibly nongap-junction intercellular
toxic.
communication (GJIC) induced by
hydrogen peroxide," says Lee. GJIC
Figure 3:
is essential for maintaining normal
Reduced Vitamin C
Oxidized Vitamin C
cell growth. Inhibition of GJIC is
strongly related to the carcinogenic
process, especially to tumor
promotion. Hydrogen peroxide, a
tumor promoter, inhibits GJIC by
changing a special protein,
connexin43. When rat liver epithelial
cells were treated with vitamin C, the
researchers report, inhibition of GJIC
induced by hydrogen peroxide was
Many suspect that it is some aspect of vitamin
prevented.”11
C’s role as an anti-oxidant which explains its
effect on cancer. Some propose that the free- Dr Lee also notes that many phytochemicals
radical scavenging property of vitamin C
found in fruits and vegetables have the same
prevents free radical damage to DNA and
effect which may begin to explain the often
leads to disease improvement. Ironically, this documented preventive effect of fruits and
has made some oncologists loath to ever
vegetables on cancer.
consider using vitamin C, even as an ancillary
treatment as it might interfere with the
Finally, apart from the enzymatic co-factor
oxidizing toxicity of their elixirs. Their
attributes and the anti-oxidant properties,
reasoning being, quite simply, “we are trying vitamin C is also a molecular messenger itself

and this mediates, likely its most well know
property, that is modulating the immune
system. Vitamin C increases cytokine
production by white blood cells, boosts
gamma interferon production and decreases
interleukin 18 production.12 Interleukin 18
itself has been found to be positively
correlated with a number of different cancers
which again provides a putative mechanism
for vitamin C’s anti-cancer effects.13

wound healing17 and, as we noted, improved
immune function. Hence at the absolute
least, far from being concerned with toxic
side effects, there are ancillary benefits to
vitamin C. These benefits would be expected
to make it an excellent palliative ancillary
treatment, and one which would of itself
improve quality of life. Indeed the evidence
suggests vitamin C might have an effect on
patient outcomes even if it did not have,
though it does, a direct anti-cancer effect.

In summary we don’t have a clear or single
hypothesis at the biochemical level for how
vitamin C acts on cancer, we do have a
number of intriguing findings and the clinical
effect may be due to a combination of a
number of the properties we just finished
discussing. More importantly than
mechanistic theories however, is that you
don’t have to scratch the medical literature
hard at all to find vitamin C, in bench, animal
and human studies, killing cancer cells.

The hostility by conventional medicine to use
of certain micronutrients, such as vitamin C,
while paying close attention to others, is both
puzzling and disturbing. Surgeons for
example will not go into surgery without
having checked (and corrected if necessary)
the blood levels of potassium, as low
potassium is known to make a patient prone
to heart arrhythmias and perhaps worse under
the stress of surgery. Given the evidence of
benefit to rectifying the common vitamin C
One last point to make before turning to the
deficiency disease states in ill patients, to
literature, Vitamin C is consumed more
ignore this, or worse yet react defensively and
rapidly when ill or stressed than in healthy
angrily, makes as much sense to me as a
conditions. Seriously ill patients, from
surgeon becoming angry at the suggestion to
whatever cause are quite often frankly
check potassium levels before surgery, that is
14
vitamin C deficient. Some researchers go so to say none.
far as to speculate whether some of the signs
of illness in critically ill patients may be
Evidence from the Medical
undiagnosed, concomitant scurvy.
Literature
Regardless, a recent randomized controlled
trial in 595 critically ill surgical patients
compared supplementation with vitamin E
he strength of evidence in medical
and one gram per day intravenous vitamin C, research may be very informally considered
to standard care. As the authors note,
to progress from test-tube studies to animal

T

“The relative risk of death in the
treatment group was 0.55 (95% CI
0.17–1.88). Similar benefits were also
evident when ICU mortality and
hospital mortality were examined.”15
That is to say the patient's receiving the antioxidants were about half as likely to die.
They also left the hospital sooner.
Correction of vitamin C deficiency is also
associated with improved mood16, better

studies to human studies, with human studies
being divided into population
studies/retrospective studies, clinical trials,
clinical trials with a control arm, and
controlled trials that are blinded. So we will
divide the presentation of evidence along
those lines rather than chronologically. For
the test-tube and animal studies I will just
provide a link to the article and its title
without further discussion but I suspect you
will get the point. We will have a little more
discussion on any human population studies
and spend the most time on the few human

trials that have been performed.
Sometime back on my blog I did a series of
posts just looking at the past year's worth of
vitamin C based research at that time. In the
last post of the series I considered what had
been seen with vitamin C in relation to
cancer. Let’s first take a look again at those
findings. Each of the linked studies is
followed by a short excerpt from the study in
the researchers’ exact words.
1) Ascorbic Acid Potentiation of
Arsenic Trioxide Anticancer Activity
Against Acute Promyelocytic
Leukemia. “These suggest that AA
(ascorbic acid) may enhance the
cytotoxicity of arsenic trioxide,
suggesting a possible future role of
ascorbic acid/Arsenic trioxide
combination therapy in patients with
APL.”
2) Arsenic trioxide and ascorbic acid
demonstrate promising activity
against primary human CLL cells in
vitro. “While both ATO and ascorbic
acid mediate cytotoxicity in CLL B
cells as single agents, the efficacy of
ATO is enhanced by ascorbic acid.”
3) High dose of ascorbic acid induces
cell death in mesothelioma cells.
“High dose of ascorbic acid induced
cell death of all mesothelioma cell
lines in a dose-dependent manner. …
intravenous administration of
ascorbic acid significantly decreased
the growth rate of mesothelioma
tumor inoculated in mice.”
4) Pharmacological ascorbic acid
suppresses syngeneic tumor growth
and metastases in hormone-refractory
prostate cancer. “Hormone-refractory
prostate cancer PAIII cells were
implanted subcutaneously into
immunologically intact, LobundWistar (LW) rats. … At the end of the
40 day experimental period, the

primary tumors were found to be
significantly reduced in weight
(p=0.026). In addition, sub-pleural
lung metastases were even more
profoundly reduced in number and
size (p=0.009). Pharmacological
doses of ascorbic acid suppress tumor
growth and metastases in hormonerefractory prostate cancer”
5) Mechanisms of ascorbate-induced
cytotoxicity in pancreatic cancer.
“Pharmacologic concentrations of
ascorbate may be effective in cancer
therapeutics. …RESULTS: .
Ascorbate decreased viability in all
pancreatic cancer cell lines but had
no effect on an immortalized
pancreatic ductal epithelial cell line.
Ascorbate decreased clonogenic
survival of the pancreatic cancer cell
lines, which was reversed by
treatment of cells with scavengers of
H(2)O(2). Treatment with ascorbate
induced a caspase-independent cell
death that was associated with
autophagy. In vivo, treatment with
ascorbate inhibited tumor growth and
prolonged survival.
CONCLUSIONS: These results show
that pharmacologic doses of
ascorbate, easily achievable in
humans, may have potential for
therapy in pancreatic cancer.”
6) Cell damage and death by
autoschizis in human bladder (RT4)
carcinoma cells resulting from
treatment with ascorbate and
menadione. “It supports the
contention that a combination of VC
(vitamin C)+VK(3), also named
Apatone, could be co-administered as
a nontoxic adjuvant with radiation
and/or chemotherapies to kill bladder
tumor cells and other cancer cells
without any supplementary risk or
side effects for patients.”
7) Ascorbate exerts anti-proliferative

effects through cell cycle inhibition
and sensitizes tumor cells towards
cytostatic drugs. “The redox-active
form of vitamin C, ascorbate, shows
therapeutic efficacy in tumor cells. …
Furthermore, ascorbate treatment
specifically enhances the cytostatic
potency of certain chemotherapeutics,
which implicates therapeutic benefit
during tumor treatment.”

Now we can’t of course discuss all 432
studies, however that was one reason I
described how to perform this search of the
medical literature. If this is an area of interest
or concern to you, repeat the search yourself,
so that you can spend as much time as you
wish looking over the same peer reviewed
research.

We can make a few quick generalizations
about all this research though. One point is
This was only one year of research mind you! that very much of this is new, much of the
Yet we see at the bench level support for the cancer related research has occurred only in
utility of vitamin C in a whole swath of
the past 10 and even more so past 5 years.
different cancers, leukemia, mesothelioma,
Secondly, going off the research that has been
prostate cancer, pancreatic cancer and bladder published to date, it is no longer a plausible or
cancer. In addition, unlike the expressed
evidence based position to hold that vitamin
concerns of vitamins getting in the way of
C is not an anti-cancer agent. Let's look at
and antagonizing more standard therapies, the just the titles of a few of the recently
evidence clearly shows that vitamin C more
published studies to demonstrate this.
often potentiates a number of conventional
chemotherapeutic agents.
The Anti-tumor Activity of Vitamin C via
Let’s broaden our search now out past just a
single year and see what else we might find,
shall we? To this end we will search the
PubMed records and because of the
tremendous amount of research in this area
we will confine our search in the following
ways. The search terms must actually be in
the title of the study and we will search on the
terms, “Vitamin C” or ascorbate or ascorbic
acid and cancer or carcinoma or tumor. So if
we go to the pubmed site and add in the limit
that the words must be in the title we can put
the following searchterm in the search box
(“Vitamin C” OR ascorbate OR “ascorbic
acid”) AND (cancer OR carcinoma OR
tumor). Doing that we get a total of 432
studies returned.
This search methodology, one can note,
would not have found references 1, 2, 3 and 7
of the seven studies we just got through
describing. So there is a lot more even than
these hundreds of studies out there.
However, this gives us a good lay of the land
of what has been published in the medical
literature on vitamin C and cancer.

the Increase of Fas (CD95) and MHC I
Expression on Human Stomach Cancer
Cell Line, SNU1.
Pharmacologic doses of ascorbic acid
repress specificity protein (Sp)
transcription factors and Sp-regulated
genes in colon cancer cells.
Inhibitory effect of vitamin C in
combination with vitamin K3 on tumor
growth and metastasis of Lewis lung
carcinoma xenografted in C57BL/6 mice.
Anti-cancer effect of pharmacologic
ascorbate and its interaction with
supplementary parenteral glutathione in
preclinical cancer models.
Aminopyrimidoisoquinolinequinone
(APIQ) redox cycling is potentiated by
ascorbate and induces oxidative stress
leading to necrotic-like cancer cell death.
Differential augmentative effects of
buthionine sulfoximine and ascorbic acid in
As2O3-induced ovarian cancer cell death:
oxidative stress-independent and
-dependent cytotoxic potentiation.
Vitamin C increases the apoptosis via upregulation p53 during cisplatin treatment

in human colon cancer cells.
Pharmacologic ascorbate synergizes with
gemcitabine in preclinical models of
pancreatic cancer.

very wide ranging anti-cancer effects and that
it is generally seen to potentiate the effect of
conventional chemotherapy treatments.

So what happened? Why isn’t there more
effort to translate these results from the testRedox-active quinones and ascorbate: an
innovative cancer therapy that exploits the tube to the patient? There are likely a number
of different currents at work which have
vulnerability of cancer cells to oxidative
stress.
delayed the potential adoption of vitamin C as
a clinical anti-cancer agent. First many of
Megadose vitamin C suppresses
these findings are new and will take a while
sulfoconjugation in human colon
to sink in. Secondly, there is often a bias on
carcinoma cell line Caco-2.
the part of some medical practitioners to
believe that something as commonplace as a
Effects of ascorbic acid and β-carotene on
vitamin can have powerful medicinal effects.
HepG2 human hepatocellular carcinoma
Such a stance seems rather irrational when
cell line.
you consider the dramatic and rapid reversal
A novel targeting modality for renal cell
of diseases such as scurvy, pellagra, beriberi
carcinoma: human osteocalcin promoteretc., with administration of the appropriate
mediated gene therapy synergistically
vitamin; nonetheless, there often remains a
induced by vitamin C and vitamin D₃.
feeling that we are dealing with “just a
Metalloporphyrin synergizes with ascorbic vitamin”, not a real drug. Thirdly, there is
little to no commercial incentive to develop
acid to inhibit cancer cell growth through
fenton chemistry.
vitamin C in any indication as it is extremely
inexpensive and non-patentable, it is, in this
Ascorbate exerts anti-proliferative effects
sense an “economic Orphan Drug” even
through cell cycle inhibition and sensitizes though it is useful in common diseases.
tumor cells towards cytostatic drugs.
Actually, if anything there is a commercial
incentive not to develop vitamin C. I believe
Selective suppression of cervical cancer
though there is one last twist to the vitamin C
Hela cells by 2-O-β-D-glucopyranosyl-Lstory that is likely at least as significant as the
ascorbic acid isolated from the fruit of
Lycium barbarum L.
others, and that is nailing down the correct
dose. To understand this let’s return now a
Low ascorbate levels are associated with
bit to the history of vitamin C.
increased hypoxia-inducible factor-1
activity and an aggressive tumor phenotype
in endometrial cancer.

We left off with one Nobel Prize winner, Dr.
Szent-Gyorgi isolating vitamin C. We can
take up our story with another two-time
Pharmacological ascorbic acid suppresses
syngeneic tumor growth and metastases in Nobel Prize winner and some would argue
hormone-refractory prostate cancer.
the greatest chemist of the 20th century, Dr.
Linus Pauling. Anyone who has struggled
Fucoidan-Vitamin C complex suppresses
through an organic chemistry textbook has
tumor invasion through the basement
Linus Pauling to thank for probably about
membrane, with scarce injuries to normal
half of what was in it. In 1959 Dr. W.
or tumor cells, via decreases in oxidative
McCormick speculated whether cancer might
stress and matrix metalloproteinases.
be a collagen deficiency disease attributable
18
So that was a small selection of the research, to vitamin C deficiency, yet another possible
from just the first two and a half pages of 22 biochemical explanation. Dr. Pauling had
pages worth of results. It is safe to say that in begun to speculate on this theory when he
became aware of the clinical work of Dr
test tube and animal studies vitamin C has

Ewan Cameron. In 1974 Dr. Cameron
published the results of an open label
prospective study that treated 50 patients with
terminal cancer with vitamin C in different
dosages and routes of administration.19 Dr.
Cameron was able to document a number of
responses in these “untreatable” cancer
patients.
This led to what remains as likely one of the,
if not the most controversial study in cancer
therapy. In 1976, Dr. Pauling and Cameron
collaborated to treat 100 terminal cancer
patients with a combination of oral vitamin C
and 10 grams intravenous (IV) vitamin C
daily. They compared these patients to a set
of 1,000 age matched controls. Remarkably
they found that vitamin C treated patients
lived on average 4.2 times (210 days versus
50 days) as long as untreated, matched
controls. This led them to conclude,

These are simply astonishing results for an
inexpensive, non-toxic therapy in a group of
patients with a variety of conventionally
untreatable cancers. Yes one can argue that it
would have been better if there had been a
randomized control group instead of matched
controls, but these results are still very
powerfully supportive of the use of vitamin C
in cancer.
Before going further I want to just point out
that up until this month these remain the only
two published prospective trials of
intravenous vitamin C in cancer and the
results were dramatically positive.

What happened next was unfortunate.
Researchers at the Mayo clinic twice
attempted to repeat these results and found no
effect.22,23. These studies were written up in
the New England Journal of Medicine and
vitamin C was dismissed as a cancer
“The results clearly indicate that this therapeutic. The two time Nobel prize
simple and safe form of medication is winning Dr. Pauling was viewed as eccentric
of definite value in the treatment of
at best and a quack at worst. Curiously
20
patients with advanced cancer.”
in 1991 Cameron published a brief
description of further evidence of benefit
After criticisms were raised about the validity from vitamin C though the manuscript
of the control group in this prospective study, detailing the actual trial was rejected
Cameron and Pauling repeated the analysis
repeatedly for publication.24
with a more rigorous selection of matched
controls. They again reported dramatic
There was, however, one crucial distinction
results from this analysis,
between the Mayo clinic studies and the
earlier Cameron/Pauling studies. In the Mayo
"The ascorbate-treated patients were clinic studies, the dose of vitamin C was
found to have a mean survival time
again 10 grams/day but was only given by the
about 300 days greater than that of
oral route, not the intravenous route.
the controls. Survival times greater
than 1 yr after the date of
The full significance of this unfortunate
untreatability were observed for 22% choice of route of administration was not
of the ascorbate-treated patients and fully apparent until 2004. At that time the
for 0.4% of the controls. The mean
results of research looking at the
survival time of these 22 ascorbatepharmacokinetics (the absorption, blood
treated patients is 2.4 yr after
levels and excretion) of vitamin C given with
reaching the apparently terminal
various routes of administration was
stage; 8 of the ascorbate-treated
published.25 What was found was that
patients are still alive, with a mean
vitamin C is not very effectively absorbed
survival time after untreatability of
from the GI tract and as larger doses of
21
3.5 yr.”
vitamin C are ingested a smaller percentage is
absorbed leading to a cap on the blood levels

of vitamin C that can be achieved via the oral
route. From this research it could be
estimated that a ten gram dose given
intravenously would lead to a peak blood
level in the range of 20 times higher than
might be expected from the same dose given
orally.

While there has been only one other
controlled trial of intravenous vitamin C in
cancer, there has been other research in the
form of case reports. Perhaps the most
rigorous of these is a write-up published in
2004 which looked at three case reports
which met all of the criteria for the National
Cancer Institutes Best Case Series
If you found that penicillin was effective in
guidelines.26 The authors document that in
pneumonia and then repeated the study giving these seriously ill cancer patients treated with
1/20th the dose of penicillin, would you
intravenous vitamin C, the clinical course of
expect to see any effect? This is the odd
the disease was dramatically superior to what
position we are in with vitamin C cancer
would historically be expected in such
research. It is, ironically enough, not that
circumstances; this includes the cure (or long
much different than what occurred with Dr.
term remission) of patients with advanced
Lind’s first clinical trial looking at vitamin C bladder cancer and stage III diffuse B cell
in scurvy. He saw an effect, then proposed a lymphoma. These case reports are part of a
formulation which had only a small fraction
larger body of less detailed and hence less
of the vitamin C used in his earlier studies.
authoritative case reports that have also been
When this formulation was ineffective, the
published documenting a beneficial effect
treatment of scurvy was set back by many
from IV vitamin C in cancer.27,28,29. In turn
decades leading to the deaths of thousands of these published case reports are a subset of
sailors.
difficult to evaluate or quantitate anecdotal
reports of physicians who have seen benefit
As I mentioned earlier vitamin C is a bit
from using IV vitamin C in cancer therapy,
unique even as vitamins go. While in general but, in light of the disdain with which this
vitamins and micronutrients are seen to be far intervention has been viewed for the past few
safer than prescription medications, there
decades, choose not to publish or publicize
aren’t any other vitamins I know of where I
their results so as to avoid controversy.
suspect that blood levels 20, 30 even 100
times greater than seen in a normal state can The population based human studies that have
be safe and medicinal. Vitamin C has
been performed have generally found no
benefits at lower levels but it also has a
correlation between vitamin C dietary intake
second gear or overdrive if you like at much and risk of cancer. This is not that surprising
higher levels. These blood levels can not be in light of the research we have been
obtained no matter how many supplements,
discussing. The medicinal levels of vitamin
oranges or rose hips one eats. The excess is C as an anti-cancer agent are tens to hundreds
simply not absorbed and if even more is
of times higher than that achievable through
present leads to diarrhea. However, for most the diet.
animals this 20-100 fold higher blood level
isn’t even the medicinal level, it is the
As I mentioned earlier, there has now, as of
walking around, day-to-day level, and
Nov, 2011 been one additional study
vitamin C isn’t a vitamin, it is a component of published looking at intravenous vitamin C
their normal metabolism. As our physiology and cancer.30 In this study of 125 late stage
is similar enough to the rest of the animal
breast cancer patients 53 were treated with
kingdom that makes use of these levels, we
7.5 grams of vitamin C/day/IV. This study
can also apparently safely benefit from, at
apparently only had 4 weeks of follow-up so
least temporarily, extremely high blood levels disease treatment efficacy data is limited.
of vitamin C.
However as regards the end-point of therapy
induced complaints, the researchers report

their results as follows.
“After adjustment for age and
baseline conditions (intensity score
before adjuvant therapy,
chemotherapy, radiotherapy), the
overall intensity score of symptoms
during adjuvant therapy and aftercare
was nearly twice as high in the
control group compared to the study
group. No side-effects of the i.v.
vitamin C administration were
documented.”30



“As research results concerning
ascorbate pharmacokinetics and its
mechanisms of action against tumor
cells have been published, and as
evidence from case studies has
continued to mount that ascorbate
therapy could be effective if the right
protocols were used, interest among
physicians and scientists has
increased.”31



“Nevertheless, recent
pharmacokinetic data suggest that
pharmacologic concentrations of
vitamin C can be achieved by
intravenous injections. Since these
concentrations exhibit anticancer
activities in vitro, this raises the
controversial question of the reevaluation of vitamin C in cancer
treatment.”32



“With unequivocal data showing that
intravenous ascorbate transiently
bypassed tight control of oral doses,
the NIH investigators had a
surprising realization.
Pharmacokinetics had been
overlooked in the cancer studies.”33

The untreated group had nearly twice the
complaints.
So at this point we have extensive to
overwhelming evidence that on the lab bench
vitamin C is a potent and broad spectrum
anti-cancer agent. We also have from
pharmacodynamic studies an understanding
that therapeutic blood levels of vitamin C as
an anti-cancer agent can in all likelihood not
be achieved by the oral route (though there is
a potential caveat to this as we will soon
discuss). We have two, one by Cameron and
one by Cameron/Pauling published trials
showing efficacy of intravenous vitamin C in
cancer. Supporting this have been a number
of published case reports, including some
which meet the best standards available as
guided by the National Cancer Institute
documenting a beneficial effect in cancer
from IV vitamin C. In opposition to this,
there has never been a clinical trial of
intravenous (note intravenous) vitamin C in
cancer that has shown no effect.

Liposomes

I

am going

to stop with
the evidence
based portion
In light of all this, and perhaps a little bit
of this writesimilar to those physicians in the years after
up but
Dr. Lind's research on vitamin C and scurvy,
continue on
some researchers are coming around to
for a bit longer
realize that there is something dramatically
on the most
important to this research even if the topic is cutting edge and speculative material. To do
not fully understood. In fact, a number of
this we first need to get a little background on
clinicians and scientists are now calling for a a recent conventional chemotherapeutic drug
re-evaluation of the role of vitamin C in
delivery system that has been developed
cancer. Here are some quotes from the recent known as a liposomal drug delivery system.
literature on this,

A liposome is simply a small sphere of lipids
arranged in a bilayer such as would be seen
with a cell membrane. While the specific
lipid used, soy lecithin, egg
phosphatidylethanolamine, etc., may vary and
the details of the manufacturing process also
alter the final liposomes, the basic idea is to
take the lipid, place it with the drug and
agitate the two, generally using sonication.
This leads to much of the drug ending up
inside the liposome where it can now be
given to a patient. So we now have liposomal
doxirubicin marketed to treat breast cancer
and liposomal daunorubicn to treat Kaposi's
sarcoma.

Granted, double the blood levels, while nice,
is still nowhere near the blood levels seen
with intravenous vitamin C. However, there
is also to be considered what may be the most
important distinction of all. For vitamin C, or
other drugs for that matter, to be of use, it is
not the amount that is floating in the blood
plasma that is most important, it is how much
of the drug actually makes it to the inside of
cells. It is the intracellular levels that will be
therapeutic.

With vitamin C, there are two active transport
channels, you might think perhaps of the
Panama canal, which regulate the flow of
vitamin C into the cell. These channels also
One reason liposomes have been used as drug limit the rate at which vitamin C can enter the
delivery agents is that they can differentially cell. The liposome though we can recall is
target tumor areas. This is because the
quite similar to the cell membrane. It is
vasculature around tumors is somewhat more believed that liposomes often merge directly
“leaky” than healthy vessels. This means that with the cell membrane, dumping their
liposomes can be engineered of a size that
contents directly into the cell interior. In such
will easily leak into cancerous areas, but not a case, one might have instead of a BB gun of
easily leave blood vessels around healthy
vitamin C consistently entering the cell
tissue.
through vitamin C channels, something more
like an occasional B52 carpet bombing run of
Very recently a company has begun
a very large one time dose of vitamin C being
manufacturing a formulation of oral,
delivered to the interior of the cell.
liposomal vitamin C. Along with the
potential cancer targeting effects there are
I apologize for the possible hyperbole and as I
additional reasons to believe this is a positive noted there is a lack of formal research
development. First, as we have noted,
available in this area. About the only
vitamin C is poorly absorbed from the GI
informal, unpublished research that I know of
tract and the efficiency of absorption
is a statement by cardiologist Dr. Thomas
decreases with increasing oral dose. In this
Levy, MD JD. Dr. Levy has used high dose
case however, it is the liposome that is being vitamin C in the treatment of a number of
absorbed. In 2006 a study was published
diseases and conditions. He states that in his
finding that liposomal vitamin C was able to opinion one gram of liposomal vitamin C is
lead to blood levels of vitamin C
clinically equivalent to ten grams not of oral
approximately twice that achievable by non
vitamin C but of intravenous vitamin C. So
liposomal oral vitamin C.34
we have documented intravenous vitamin C
The kidney also clears vitamin C from the
leads to effects at least an order of magnitude
blood stream, excreting it in the urine and
greater than conventional oral forms and Dr.
decreasing blood levels. While in the absence Levy feels that liposomal vitamin C is
of data it is purely speculative, as the vitamin clinically an order of magnitude more
C is insulated within the liposome, one might powerful than intravenous vitamin C. Wow.
at least reasonably wonder whether elevated Dr. Levy is a consultant to LivOn laboratories
blood levels would be sustained longer with a that manufactures a formulation of liposomal
liposomal formulation.
vitamin C and as I said there is no formal
research to date to validate these claims.

However, Dr. Levy has authored multiple
authoritative books on the therapeutic utility
of vitamin C and is one of a handful of
individuals with extensive clinical experience
in the area. He may reasonably be considered
a world authority on the topic, which makes
his statement all the more incredible
sounding. To my knowledge LivOn Labs is
currently the only manufacturer of liposomal
vitamin C though I have read of at least one
other company looking to follow suit.

It does appear to me obvious at this point that
the evidence in the medical literature
indicates that vitamin C is useful in the
treatment of cancer. When one compares the
tragic side effect profiles of many
conventional chemotherapeutics to the
expected additional ancillary benefits from
additional vitamin C it seems quite irrational
not to recommend its use. The blood levels
achieved with non-liposomal oral vitamin C
are such that, while likely palliatively
LivOn laboratory's liposomal vitamin C is
benefiting quality of life there is not evidence
widely available without prescription on
in the literature that this intervention would
Amazon and elsewhere. I have also seen
have an effect on disease course. The
videos on how to homebrew liposomal
evidence for intravenous vitamin C is both
products using an ultrasonic utensils cleaner dramatically positive and cruelly sparse at
and some soy lecithin but have no idea what this point. If earlier findings hold up, such an
sort of product you would end up with so you intervention likely has greater therapeutic
are on your own with that route.
effect than the best available standard of care
in many if not most instances. Liposomal
I do not want to conclude this monograph as vitamin C is quite speculative at this point,
though we have obviously found the “cure for however its possible promise seems like
cancer.” I would say, as I have just
science fiction of years past, too much to
documented, that there is evidence that
believe. If by chance Dr. Levy’s dramatic
intravenous vitamin C is useful in cancer
clinical experience is validated in a more
therapy. At the same time, the clinical use of formal research setting, it might be noted that
intravenous and liposomal vitamin C is an
2 grams of liposomal C would be clinically
area that is in great need of further study.
equivalent to 20 grams IV/day, or twice the
Given our new understanding of the
dose at which Pauling and Cameron were
pharmacodynamics of vitamin C, previous
seeing such dramatic effects on cancer.
studies were seen to show a dramatic effect of
vitamin C on cancer dependent on sufficient As a licensed physician, I would not
blood levels of vitamin C being obtained.
recommend any one in good health take more
There are, however, very few confirmatory
than the currently recommended daily limit of
clinical studies to provide the level of
2 grams of vitamin C per day unless under a
assurance one might hope for. Unfortunately, physician’s supervision. I will personally
because of lack of funds and academic and
attest that I have taken as much as 4 grams in
political climates, necessary studies will be
a day of liposomal C without side effects.
slowly forthcoming at best.
Considering the wealth of supportive bench
While none of them, to my knowledge,
research, the finding of potentiating effects
employed intravenous vitamin C, in a cruel
with most conventional chemotherapeutics,
twist of fate, both Dr. Cameron and Pauling
the, only positive, studies with IV
died from prostate cancer, Cameron at age 70, administration, and the track record of safety
Pauling at age 93. In addition, one of their
of even high dose vitamin C, if I or someone I
fiercest critics, Dr. Charles Moertel who was knew had cancer I would give IV and
lead author on one of the Mayo clinic studies liposomal vitamin C much more than a
finding no effect in cancer from oral vitamin passing thought.
C also died from cancer at age 66.

Ciao,
Paul
Paul Maher, MD MPH

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